Complement C3 Variant and the Risk of Age-Related Macular Degeneration

doi:10.1056/NEJMoa072618

Volume 357:553-561		August 9, 2007		Number 6

Complement C3 Variant and the Risk of Age-Related Macular Degeneration

John R.W. Yates, F.R.C.P., Tiina Sepp, Ph.D., Baljinder K. Matharu, M.Sc., Jane C. Khan, F.R.C.Ophth., Deborah A. Thurlby, R.G.N., M.Sc., Humma Shahid, M.R.C.Ophth., David G. Clayton, M.A., Caroline Hayward, Ph.D., Joanne Morgan, B.Sc., Alan F. Wright, Ph.D., F.R.C.P., Ana Maria Armbrecht, Ph.D., F.R.C.S., Baljean Dhillon, F.R.C.S., F.R.C.Ophth., Ian J. Deary, Ph.D., F.R.C.P.E., Elizabeth Redmond, R.G.N., M.Sc., Alan C. Bird, M.D., F.R.C.S., Anthony T. Moore, F.R.C.S., F.R.C.Ophth., for the Genetic Factors in AMD Study Group

Full Text

PDF

PDA Full Text

PowerPoint Slide Set

Add to Personal Archive

Add to Citation Manager

Notify a Friend

E-mail When Cited

E-mail When Letters Appear

PubMed Citation

ABSTRACT

Background Age-related macular degeneration is the most commoncause of blindness in Western populations. Susceptibility isinfluenced by age and by genetic and environmental factors.Complement activation is implicated in the pathogenesis.

Methods We tested for an association between age-related maculardegeneration and 13 single-nucleotide polymorphisms (SNPs) spanningthe complement genes C3 and C5 in case subjects and controlsubjects from the southeastern region of England. All subjectswere examined by an ophthalmologist and had independent gradingof fundus photographs to confirm their disease status. To testfor replication of the most significant findings, we genotypeda set of Scottish cases and controls.

Results The common functional polymorphism rs2230199 (Arg80Gly)in the C3 gene, corresponding to the electrophoretic variantsC3S (slow) and C3F (fast), was strongly associated with age-relatedmacular degeneration in both the English group (603 cases and350 controls, P=5.9x10^–5) and the Scottish group (244cases and 351 controls, P=5.0x10^–5). The odds ratio forage-related macular degeneration in C3 S/F heterozygotes ascompared with S/S homozygotes was 1.7 (95% confidence interval[CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6(95% CI, 1.6 to 4.1). The estimated population attributablerisk for C3F was 22%.

Conclusions Complement C3 is important in the pathogenesis ofage-related macular degeneration. This finding further underscoresthe influence of the complement pathway in the pathogenesisof this disease.

Source Information

From the Cambridge Institute for Medical Research, University of Cambridge, Cambridge (J.R.W.Y., T.S., B.K.M., J.C.K., D.A.T., H.S., D.G.C.); the Medical Research Council Human Genetics Unit, Edinburgh (C.H., J.M., A.F.W.); the Princess Alexandra Eye Pavilion, Edinburgh (A.M.A., B.D.); the University of Edinburgh, Edinburgh (I.J.D.); the Institute of Ophthalmology, University College London (E.R., A.C.B., A.T.M.); and Moorfields Eye Hospital, London (A.C.B., A.T.M.) — all in the United Kingdom.

Drs. Yates and Sepp contributed equally to this article.

This article (10.1056/NEJMoa072618) was published at www.nejm.org on July 18, 2007.

Address reprint requests to Dr. Yates at the Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Bldg., Box 139, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom, or at jrwy1{at}cam.ac.uk.

Full Text of this Article

This article has been cited by other articles:

Fleckenstein, M., Adrion, C., Schmitz-Valckenberg, S., Gobel, A. P., Bindewald-Wittich, A., Scholl, H. P. N., Mansmann, U., Holz, F. G., for the FAM Study Group, (2010). Concordance of Disease Progression in Bilateral Geographic Atrophy Due to AMD. IOVS 51: 637-642 [Abstract] [Full Text]
Farwick, A., Wellmann, J., Stoll, M., Pauleikhoff, D., Hense, H.-W. (2010). Susceptibility Genes and Progression in Age-Related Maculopathy: A Study of Single Eyes. IOVS 51: 731-736 [Abstract] [Full Text]
Cui, L., Zhou, H., Yu, J., Sun, E., Zhang, Y., Jia, W., Jiao, Y., Snellingen, T., Liu, X., Lim, A., Wang, N., Liu, N. (2010). Noncoding Variant in the Complement Factor H Gene and Risk of Exudative Age-Related Macular Degeneration in a Chinese Population. IOVS 51: 1116-1120 [Abstract] [Full Text]
Lederman, M., Weiss, A., Chowers, I. (2010). Association of Neovascular Age-Related Macular Degeneration with Specific Gene Expression Patterns in Peripheral White Blood Cells. IOVS 51: 53-58 [Abstract] [Full Text]
Hecker, L. A., Edwards, A. O., Ryu, E., Tosakulwong, N., Baratz, K. H., Brown, W. L., Issa, P. C., Scholl, H. P., Pollok-Kopp, B., Schmid-Kubista, K. E., Bailey, K. R., Oppermann, M. (2010). Genetic control of the alternative pathway of complement in humans and age-related macular degeneration. Hum Mol Genet 19: 209-215 [Abstract] [Full Text]
Wasmuth, S., Lueck, K., Baehler, H., Lommatzsch, A., Pauleikhoff, D. (2009). Increased Vitronectin Production by Complement-Stimulated Human Retinal Pigment Epithelial Cells. IOVS 50: 5304-5309 [Abstract] [Full Text]
Schmid-Kubista, K. E., Tosakulwong, N., Wu, Y., Ryu, E., Hecker, L. A., Baratz, K. H., Brown, W. L., Edwards, A. O. (2009). Contribution of Copy Number Variation in the Regulation of Complement Activation Locus to Development of Age-Related Macular Degeneration. IOVS 50: 5070-5079 [Abstract] [Full Text]
Borooah, S, Collins, C, Wright, A, Dhillon, B (2009). Late-onset retinal macular degeneration: clinical insights into an inherited retinal degeneration. Postgrad. Med. J. 85: 495-500 [Abstract] [Full Text]
Ni, J., Yuan, X., Gu, J., Yue, X., Gu, X., Nagaraj, R. H., Crabb, J. W., The Clinical Genomic and Proteomic AMD Study Group, (2009). Plasma Protein Pentosidine and Carboxymethyllysine, Biomarkers for Age-related Macular Degeneration. Mol. Cell. Proteomics 8: 1921-1933 [Abstract] [Full Text]
Yang, P., Tyrrell, J., Han, I., Jaffe, G. J. (2009). Expression and Modulation of RPE Cell Membrane Complement Regulatory Proteins. IOVS 50: 3473-3481 [Abstract] [Full Text]
Park, K. H., Fridley, B. L., Ryu, E., Tosakulwong, N., Edwards, A. O. (2009). Complement Component 3 (C3) Haplotypes and Risk of Advanced Age-Related Macular Degeneration. IOVS 50: 3386-3393 [Abstract] [Full Text]
Rohrer, B., Long, Q., Coughlin, B., Wilson, R. B., Huang, Y., Qiao, F., Tang, P. H., Kunchithapautham, K., Gilkeson, G. S., Tomlinson, S. (2009). A Targeted Inhibitor of the Alternative Complement Pathway Reduces Angiogenesis in a Mouse Model of Age-Related Macular Degeneration. IOVS 50: 3056-3064 [Abstract] [Full Text]
Woodward, O. M., Kottgen, A., Coresh, J., Boerwinkle, E., Guggino, W. B., Kottgen, M. (2009). Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc. Natl. Acad. Sci. USA 106: 10338-10342 [Abstract] [Full Text]
Gu, J., Pauer, G. J. T., Yue, X., Narendra, U., Sturgill, G. M., Bena, J., Gu, X., Peachey, N. S., Salomon, R. G., Hagstrom, S. A., Crabb, J. W., Clinical Genomic and Proteomic AMD Study Group, (2009). Assessing Susceptibility to Age-related Macular Degeneration with Proteomic and Genomic Biomarkers. Mol. Cell. Proteomics 8: 1338-1349 [Abstract] [Full Text]
Seddon, J. M., Reynolds, R., Maller, J., Fagerness, J. A., Daly, M. J., Rosner, B. (2009). Prediction Model for Prevalence and Incidence of Advanced Age-Related Macular Degeneration Based on Genetic, Demographic, and Environmental Variables. IOVS 50: 2044-2053 [Abstract] [Full Text]
Francis, P J, Hamon, S C, Ott, J, Weleber, R G, Klein, M L (2009). Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J. Med. Genet. 46: 300-307 [Abstract] [Full Text]
Montes, T., Tortajada, A., Morgan, B. P., Rodriguez de Cordoba, S., Harris, C. L. (2009). Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc. Natl. Acad. Sci. USA 106: 4366-4371 [Abstract] [Full Text]
Zhou, J., Kim, S. R., Westlund, B. S., Sparrow, J. R. (2009). Complement Activation by Bisretinoid Constituents of RPE Lipofuscin. IOVS 50: 1392-1399 [Abstract] [Full Text]
Borooah, S, Collins, C, Wright, A, Dhillon, B (2009). Late-onset retinal macular degeneration: clinical insights into an inherited retinal degeneration. Br J Ophthalmol 93: 284-289 [Abstract] [Full Text]
Varagunam, M., Yaqoob, M. M., Dohler, B., Opelz, G. (2009). C3 Polymorphisms and Allograft Outcome in Renal Transplantation. NEJM 360: 874-880 [Abstract] [Full Text]
McKay, G. J., Silvestri, G., Patterson, C. C., Hogg, R. E., Chakravarthy, U., Hughes, A. E. (2009). Further Assessment of the Complement Component 2 and Factor B Region Associated with Age-Related Macular Degeneration. IOVS 50: 533-539 [Abstract] [Full Text]
Fremeaux-Bacchi, V., Miller, E. C., Liszewski, M. K., Strain, L., Blouin, J., Brown, A. L., Moghal, N., Kaplan, B. S., Weiss, R. A., Lhotta, K., Kapur, G., Mattoo, T., Nivet, H., Wong, W., Gie, S., de Ligny, B. H., Fischbach, M., Gupta, R., Hauhart, R., Meunier, V., Loirat, C., Dragon-Durey, M.-A., Fridman, W. H., Janssen, B. J. C., Goodship, T. H. J., Atkinson, J. P. (2008). Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112: 4948-4952 [Abstract] [Full Text]
Yang, Z., Stratton, C., Francis, P. J., Kleinman, M. E., Tan, P. L., Gibbs, D., Tong, Z., Chen, H., Constantine, R., Yang, X., Chen, Y., Zeng, J., Davey, L., Ma, X., Hau, V. S., Wang, C., Harmon, J., Buehler, J., Pearson, E., Patel, S., Kaminoh, Y., Watkins, S., Luo, L., Zabriskie, N. A., Bernstein, P. S., Cho, W., Schwager, A., Hinton, D. R., Klein, M. L., Hamon, S. C., Simmons, E., Yu, B., Campochiaro, B., Sunness, J. S., Campochiaro, P., Jorde, L., Parmigiani, G., Zack, D. J., Katsanis, N., Ambati, J., Zhang, K. (2008). Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration. NEJM 359: 1456-1463 [Abstract] [Full Text]
Ghannam, A., Pernollet, M., Fauquert, J.-L., Monnier, N., Ponard, D., Villiers, M.-B., Peguet-Navarro, J., Tridon, A., Lunardi, J., Gerlier, D., Drouet, C. (2008). Human C3 Deficiency Associated with Impairments in Dendritic Cell Differentiation, Memory B Cells, and Regulatory T Cells. J. Immunol. 181: 5158-5166 [Abstract] [Full Text]
Ramo, K., Cashman, S. M., Kumar-Singh, R. (2008). Evaluation of Adenovirus-Delivered Human CD59 as a Potential Therapy for AMD in a Model of Human Membrane Attack Complex Formation on Murine RPE. IOVS 49: 4126-4136 [Abstract] [Full Text]
Ng, T. K., Chen, L. J., Liu, D. T. L., Tam, P. O. S., Chan, W. M., Liu, K., Hu, Y. J., Chong, K. K. L., Lau, C. S. L., Chiang, S. W. Y., Lam, D. S. C., Pang, C. P. (2008). Multiple Gene Polymorphisms in the Complement Factor H Gene Are Associated with Exudative Age-Related Macular Degeneration in Chinese. IOVS 49: 3312-3317 [Abstract] [Full Text]
Spencer, K. L., Olson, L. M., Anderson, B. M., Schnetz-Boutaud, N., Scott, W. K., Gallins, P., Agarwal, A., Postel, E. A., Pericak-Vance, M. A., Haines, J. L. (2008). C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet 17: 1821-1824 [Abstract] [Full Text]
Hakobyan, S., Harris, C. L., Tortajada, A., Goicochea de Jorge, E., Garcia-Layana, A., Fernandez-Robredo, P., Rodriguez de Cordoba, S., Morgan, B. P. (2008). Measurement of Factor H Variants in Plasma Using Variant-Specific Monoclonal Antibodies: Application to Assessing Risk of Age-Related Macular Degeneration. IOVS 49: 1983-1990 [Abstract] [Full Text]
Ormsby, R. J., Ranganathan, S., Tong, J. C., Griggs, K. M., Dimasi, D. P., Hewitt, A. W., Burdon, K. P., Craig, J. E., Hoh, J., Gordon, D. L. (2008). Functional and Structural Implications of the Complement Factor H Y402H Polymorphism Associated with Age-Related Macular Degeneration. IOVS 49: 1763-1770 [Abstract] [Full Text]
Edwards, A. O., Chen, D., Fridley, B. L., James, K. M., Wu, Y., Abecasis, G., Swaroop, A., Othman, M., Branham, K., Iyengar, S. K., Sivakumaran, T. A., Klein, R., Klein, B. E. K., Tosakulwong, N. (2008). Toll-like Receptor Polymorphisms and Age-Related Macular Degeneration. IOVS 49: 1652-1659 [Abstract] [Full Text]
Liew, G., Mitchell, P., Wong, T. Y., Iyengar, S. K., Wang, J. J. (2008). CKD Increases the Risk of Age-Related Macular Degeneration. J. Am. Soc. Nephrol. 19: 806-811 [Abstract] [Full Text]
Haines, J. L., Spencer, K. M., Pericak-Vance, M. A. (2007). Bringing the genetics of macular degeneration into focus. Proc. Natl. Acad. Sci. USA 104: 16725-16726 [Full Text]
Coffey, P. J., Gias, C., McDermott, C. J., Lundh, P., Pickering, M. C., Sethi, C., Bird, A., Fitzke, F. W., Maass, A., Chen, L. L., Holder, G. E., Luthert, P. J., Salt, T. E., Moss, S. E., Greenwood, J. (2007). Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc. Natl. Acad. Sci. USA 104: 16651-16656 [Abstract] [Full Text]
Burke, W., Psaty, B. M. (2007). Personalized Medicine in the Era of Genomics. JAMA 298: 1682-1684 [Full Text]

Comments and questions? Please contact us.